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Drug Distribution.pdf
- 1. Prof. Shaikh Abusufiyan Assistant Professor, AIKTC-School of Pharmacy, New Panvel-410206 Drug Distribution Pharma Learning Forever
- 2. At the end of this e-learning session you are able to… A. Explain factor affecting drug distribution.
- 3. Distribution • The extent of distribution of a drug depends on its • Lipid solubility • Ionization at physiological pH • Extent of binding to plasma and tissue proteins • Presence of tissue-specific transporters • and differences in regional blood flow.
- 4. • Movement of drug proceeds Until an equilibrium is established between unbound drug in plasma and tissue fluids.
- 5. Apparent volume of distribution (V) • Assuming that the body behaves as a “single homogeneous compartment with volume “V” • It means it is that volume --> that would accommodate all the drug in the body.
- 6. Factor affecting volume of distribution (V) • Lipid-insoluble drugs --> do not enter cells- Therefore “V” is approximately equal to volume of extracellular fluid e.g. streptomycin, gentamicin 0.25 L/kg. • Drugs extensively bound to plasma proteins --> are largely restricted to the vascular compartment and have low values e.g. diclofenac and warfarin (99 % bound), V = 0.75L /kg.
- 7. • Drugs sequestrated in other tissues --> may have V much more than total body water or even body mass e.g. digoxin 6L/kg. • Most of the drugs are present in other tissues plasma concentration is low. In case of poisoning, drugs with large volumes of distribution are not easily removed by haemodialysis.
- 8. • Pathological states e.g. congestive heart failure, uraemia, cirrhosis of liver etc. --> can alter the “V” of many drugs by altering: • distribution of body water • permeability of membranes • binding proteins • accumulation of metabolites that displace the drug from binding sites.
- 9. Illustration of concept of V
- 10. Redistribution • Redistribution: Highly lipid-soluble drugs get initially distributed to organs --> with high blood flow i.e. brain, heart, kidney etc. • Later, it is redistributed into less vascular but more bulky tissues (muscle, fat) & it lead to --> fall in plasma concentration.
- 11. • If the site of action of the drug was in one of the highly perfused organs Redistribution results in termination of drug action. Greater the lipid solubility of the drug Faster is its redistribution.
- 12. • Eg. Anaesthetic action of thiopentone sod. injected i.v. is --> terminated in few minutes due to redistribution. Solution: • However, when the same drug is given repeatedly or continuously over long periods the sites get saturated And the drug becomes longer acting.
- 13. Penetration into brain and CSF: • The capillary endothelial cells in brain have tight junctions --> lack large intercellular pores. • Further, neural tissue --> covers the capillaries. • Together they constitute --> blood-brain barrier.
- 14. Usual capillaries & brain capillaries
- 15. • A similar blood-CSF barrier is --> located in the choroid plexus: tight junctions. • Both these barriers are lipoidal --> limit the entry of nonlipid-soluble drugs e.g. Streptomycin, neostigmine etc.
- 16. • Therefore, Only lipid-soluble drugs --> able to penetrate and have action on the central nervous system. • Inflammation of meninges --> increases the permeability of these barriers. • Some drugs accumulate in the brain --> by utilizing the transporters for endogenous substances.
- 17. Enzymatic blood-brain barrier: • Some enzymes such as • Monoamine oxidase (MAO) • Cholinesterase • And some other enzymes are present in the capillary walls or in the cells lining the brain. Do not allow catecholamines, 5-HT, acetylcholine etc. to enter brain in the active form.
- 18. Other sites for distribution of lipid insoluble drugs in brain: • The blood-brain barrier is deficient at the • CTZ in the medulla oblongata • And at certain periventricular sites (anterior hypothalamus). Therefore, even lipid-insoluble drugs are emetic
- 19. Q&A Q.1 Enlist distribution dependent factors. Q.2 What is apparent volume of distribution?. Q.3 Blood-brain barrier and brain-CSF barriers limit entry of……………..drugs. Q4. Name part of brain where even lipid insoluble drugs can also penetrate. Copyright @shaikhabusufiyan2021
- 20. Distribution across placenta • Passage across placenta • Placental membranes (lipoidal) free passage restrict • lipophilic drugs hydrophilic drugs.
- 21. • Placenta contain two type of transporter 1. The placental efflux P-gp (efflux transporter) limit foetal exposure to maternally administered drugs. 2. Influx transporters- Drug is transported into the placenta.
- 22. Non-lipid-soluble drugs, when present in 1. high concentration or 2. for long periods in maternal circulation Enter into the foetus Placenta is an incomplete barrier and almost any drug taken by the mother can affect the foetus or the new-born.
- 23. Plasma-protein drug binding • Drugs possess physicochemical affinity for plasma proteins. • It bind to • Acidic drugs plasma albumin • Basic drugs alpha 1 acid glycoprotein. • Albumin binding is quantitatively more important.
- 24. • It is an Saturable process. • Binding may be lower when large amounts of the drug are given.
- 25. Clinical implication of plasma protein binding 1. Highly plasma protein bound drugs restricted to the vascular compartment Smaller volume of distribution v
- 26. Drugs highly bound to plasma protein
- 27. (ii) The bound fraction is not available for action, unless it is free. • Bound drug Free drug • Therefore plasma protein binding --> provide temporary storage to the drugs in vascular compartment.
- 28. (iii) High degree of protein binding generally makes the drug long acting, because bound fraction is not available for metabolism or excretion, unless it is actively extracted by liver or kidney tubules.
- 29. iv. Plasma concentrations of the drug = Concentration of bound + Concentration of free drug.
- 30. Displacement interactions V. One drug can bind to many sites on the albumin molecule. Conversely, more than one drug can bind to the same site. It lead to displacement interactions: drug bound with higher affinity will displace that bound with lower affinity.
- 31. • Two highly bound drugs do not necessarily displace each other. • e.g. probenecid and indomethacin are highly bound to albumin but do not displace each other. • Similarly, acidic drugs do not generally displace basic drugs and vice a versa
- 32. Clinically important displacement interactions • Salicylates displace sulfonylureas. • Indomethacin, phenytoin displace warfarin. • Sulfonamides and vit K displace • bilirubin • (kernicterus in neonates). • Salicylates displace methotrexate
- 33. (vi) In hypoalbuminemia binding is reduced high concentrations of free drug e.g. phenytoin and furosemide.
- 34. • Some diseases may also alter drug binding • Eg. propranolol binding is increased in • Pregnant women • And in patients with inflammatory disease.
- 35. Tissue storage • Drugs may also accumulate in specific organs by active transport or get bound to specific tissue constituents. • Drugs sequestrated in various tissues large volume of distribution long duration of action.
- 36. Storage toxicity • Some may exert local toxicity due to high concentration • e.g. Tetracyclines on bone and teeth Chloroquine on retina. • Drugs may also selectively bind to specific intracellular organelle e.g. Tetracycline to mitochondria
- 37. Drug concentrated in tissue
- 38. Reference: • K D Tripathi. Essentials of Medical Pharmacology. Seventh Edition. Jaypee Publication. Page no:18-22.
- 39. Disclaimer (Images) • The images used in this presentation are found from different sources all over the Internet, and are assumed to be in public domain and are displayed under the fair use principle for education purpose. Copyright @ Presentation • The said presentation is copyright under Copyright @shaikhabusufiyan2022 • The presentation is for education purpose only, don’t use the same for any legal perspective.
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